The frequency and duration of heat waves have increased significantly over the last 50 years in the United States. Heat waves killed more people during a typical year than floods, tornadoes, and earthquakes combined. The health impacts of extreme heat events are likely to increase as a result of the synergistic effects of a warming climate, urbanization, and the aging of the population. Older people are especially vulnerable to heat waves, not only because of age and preexisting medical conditions, but also because of the multiple medications they take for comorbid conditions. Several researchers have proposed hypotheses about interactions between heat waves and medication use. Given the high prevalence of medication use and polypharmacy among older persons, it is important to understand the combined impact of medication use and heat waves. A multidisciplinary team of experts in climatology, pharmacoepidemiology, and health services and outcomes research will work collaboratively to design and conduct analyses to (1) identify and quantify the potential magnifying effects of commonly used prescription medications on the short- and long-term health consequences of heat waves and the heat-related side effects of these medications, and (2) quantify health care resource use (hospitalizations, intensive care unit stays, and costs) during heat waves, considering both the direct effects of heat waves and the effects of drug-heat wave interactions. To conduct the proposed analyses, we will link several existing data sources, including temperature, humidity, heat index, and air pollution data, data on health care resource use in the Medicare program, and longitudinal data on pharmacy dispensing. The drug categories of interest include antipsychotics, antidepressants, stimulants, diuretics, antihypertensive drugs, antiepileptic drugs, anti-Parkinson drugs, lipid-lowering agents, and other medications with significant anticholinergic properties that may increase the risk of heat stroke by disturbing thermoregulation, inducing fluid and electrolyte imbalance, or decreasing thirst or that have known adverse effects that may be magnified by extreme heat conditions. The conceptual framework and methods being developed in the proposal can be adapted to other populations and data sources, including other climate data and electronic health records. At the completion of this preliminary study, we will have provided the first clear analyses on interactions between heat waves and commonly used prescription drugs among older patients. These data may inform clinicians, policy makers, patients, and other key stakeholders by characterizing the scope of the problem and can be further expanded to assist in the development of tailored guides and adaptive strategies for vulnerable populations.